1. Field of the Invention
The present invention relates to agent for suppressing infection and proliferation of human immunodeficiency syndrome virus (HIV-1), which infects immunocompetent cells such as macrophage or dendritic cell and causes destruction of immune system. More particularly, the present invention relates to use of agent for suppressing infection and proliferation of human immunodeficiency syndrome virus, agent of which suppresses infecting and proliferating human immunodeficiency syndrome virus to M type macrophage derived from human monocytes.
2. Description of Related Art
More than 40 million peoples have been infected with human immunodeficiency syndrome virus (HIV-1), and among them, about 5 million subjects were estimated to develop acquired immune deficiency syndrome (AIDS). AIDS is really a world wide infectious disease. Highly active antiretroviral therapy (HAART) for patients with HIV-1 has appeared in the early 1990's. As a result of application in the clinical field, large therapeutic effect was obtained such as decreasing viral counts in plasma of patients with AIDS and recognizing recovery of number of CD4.
However, on the other hand, it is apprehensive that macrophage (MΦ) directed virus is remained in the reticuloendothelial tissues1),2) and resistant strain to HAART is observed in patients who received HAART in about half year to several years after HAART. Further, since the cost for treatment by HAART is expensive, the treatment is given priority to peoples in the advanced countries, and peoples in the under developing countries can not receive such the treatment due to a disparities in economic power between advanced countries and the under developing countries where there are more than 80% of patients with HIV in the world, and such treatment could not contribute to interrupt international distribution of virus, as a result, multiple combination therapy is required in order to suppress appearance of resistant strains, and patients who are dropped out from the treatment due to abdominal symptom and hematopoietic injury are reported, consequently, limits in the medical and social application for HAART are pointed out.
HIV-1 is a virus which infects to immunocompetent cells such as macrophage and dendritic cell to destroy the immune system. As the results of recent research studies, it is becoming clear that the infection and proliferation of HIV-1 in the macrophage play important roles on the maintenance of infection and the development of pathogenesis of HIV-13), consequently, development of new drugs which inhibit infection and proliferation of HIV-1 in the macrophage is expected.
Although large numbers of infectious experiments on HIV-1 in the macrophage were performed, many studies were carried out using the macrophage cell strains, as the results, the experimental results using such cell strains did not always reflect function of tissue macrophage in vivo. Akagawa et al. succeeded differential induction of two types of the macrophage proceeding proliferation of HIV-1 and the macrophage suppressing proliferation of HIV-1 from the monocytes, further demonstrated that the macrophage suppressing the proliferation could be a model for human alveolar macrophage, as a result, analysis of infection, proliferation and a mechanism for suppression of the proliferation of HIV-1 was made possible in the system similar to the macrophage in vivo4)-9).
In addition, macrolides have known that it is effective for treatment of diffuse panbronchiolitis (DPB) and diseases of otorhinology field and a mechanism of action thereof is known, in addition to antibiotic action, to be an induction of antiunflammatory actions10). Especially, as a result of examining accumulation of macrolides in tissues, there is a report indicating several hundreds to a thousand times of accumulation were observed in the macrophage as compared with the peripheral lymphocytes, consequently, action of the macrolides on macrophage is thought to be important.
Based on the above background, we have thought that development of drugs supplementing disadvantages of HAART, suppressing infection and proliferation of HIV-1 in the macrophage and aiming at exclusion of the macrophage directed HIV-1 from the lymphoid reticuloendothelial system, especially development of inexpensive chemotherapeutic agents from the standpoint of therapeutic strategy against AIDS in view of the world wide level is useful for treatment of patients with HIV-1.
We have studied that whether the known macrolides derivatives have actions for inhibiting infection and proliferation of HIV-1 or not, and quite surprisingly found that they have inhibitory actions against infection and proliferation of HIV-1 in the macrophage, and demonstrated that the inhibitory action against the proliferation is exhibited by suppressing expression of tyrosine kinase Hck protein in the macrophage which is essential for viral growth and suppressing activation of P38MAPK, and completed the present invention.
An object of the present invention is to provide use of agent for suppressing infection and proliferation of human immunodeficiency syndrome virus useful for treatment of patients with HIV-1 infection by inexpensive chemotherapeutic agent as well as useful as a supplemental agent in the HAART.